Editorial

Welcome to a new series of articles on stem cell genomics to be published in this
and upcoming issues of Genome Medicine. These contributions sample just a few of the many exciting developments in the field
of stem cells and genomic research and project ahead to future advances that will
make a clear imprint on medicine.

Simply put, stem cells are defined by two properties: self-renewal, the generation
of more identical cells, and developmental potency, the capacity to give rise to more
differentiated cells. Stem cells come in different 'flavors'. Blood-forming (hematopoietic)
stem cells (HSCs), which sustain blood formation through our entire lives, are restricted
in their developmental potential to generate only blood cell lineages. On the other
hand, embryonic stem (ES) cells can produce the entire repertoire of cells of the
body, a property called pluripotency. Although the varieties of stem cells are diverse,
it is increasingly evident that fundamental principles and mechanisms underlie self-renewal
and differentiation, such that disparate research communities are brought together
by common biological themes.

From all the recent excitement in the media about new developments in stem cells,
one might think that stem cells were hitherto unknown. Nothing can be further from
the truth. Indeed, bone marrow transplantation (BMT), a life-saving procedure for
which the Nobel Prize was awarded to E Donnall Thomas in 1990, has been used for more
than three decades to treat aplastic anemia and leukemia [1]. Remarkably, BMT was developed empirically through animal and human experimentation
before the identification and characterization of HSCs. The extraordinary history
of BMT and its clinical development have much to teach us now about how to turn current
strategies in the stem cell field into new therapies. For example, although first
conceived to treat blood disorders, BMT is gaining momentum in the treatment of non-hematological
and non-malignant diseases [2].

Current excitement regarding stem cells rests on several converging themes. The derivation
of ES cells, first of mouse and then of human origin, provided a platform for the
study of pluripotency and the in vitro generation of different cell types. Recent advances in our understanding of the molecular
mechanisms underlying lineage determination and differentiation have fueled methods
for the interconversion of cells of different lineages. In the most dramatic version
of such cellular gymnastics, Shinya Yamanaka and colleagues [3] demonstrated that a small cocktail of regulatory factors can turn virtually any somatic
cell into a pluripotent, ES-like cell in a process known as cellular reprogramming.
These induced pluripotent stem (iPS) cells have become the focus of brigades of investigators,
particularly because they provide a system in which to generate pluripotent cells
from an individual of a specific genetic constitution (disease state), giving birth
to the notion of 'disease in the dish'.

Improved high-throughput methods, mostly supported by enhanced protein and DNA sequencing
platforms, are being used to characterize the cellular proteome, transcriptome, and
epigenome (DNA methylation and histone modifications) in comprehensive and exhaustive
detail. The vast data from these approaches provide a framework in which to consider
the molecular mechanisms underlying cell fate decisions. As cell choice is at the
heart of stem cell biology, this knowledge base will guide future research into manipulating
normal or disease-related cells for ultimate therapeutic benefit.

This series of articles provides a sense of the breadth and scope of the contemporary
stem cell scene. The field touches nearly every corner of medical science. What can
we reasonably expect in the coming years? Making predictions is a risky business;
nonetheless, I will try. First, the exploitation of 'disease in a dish' should lead
to critical new insights into disease processes and stimulate new therapeutic strategies.
Second, we should anticipate the development of new therapies based on the stimulation
of endogenous stem cells for tissue repair or for reversing the effects of aging,
perhaps well before the development of cells as regenerative medicine products. Third,
the use of specific cell types produced from human pluripotent cells, especially of
defined genotypes, should improve the screening of drug toxicity and reduce the overall
costs of drug development. Fourth, the connections between epigenetic regulation in
pluripotent cells and cancer cells will forge innovative approaches to epigenetic
therapy of malignant conditions, and possibly the contribution of epigenetic modulation
to non-malignant conditions. Fifth, ex vivo methods for the generation of specific cell types from pluripotent cells or by direct
lineage interconversion should drive bioengineering and fuel the next advances in
the creation of artificial organs. And finally, with an increased ability to manipulate
and generate stem cells of various tissues will come the potential to use gene modification
to correct genetic defects or enhance cellular capacities. Such work should stimulate
advances in somatic gene therapy of disease.

Although the applications of stem cell biology may be dazzling, it is critical to
support fundamental work in the stem cell arena, as only that will ensure a solid
foundation for clinical translation and lead to those unexpected discoveries that
drive future innovation. We hope that this series on translational stem cell genomics
provides a glimpse into this remarkable field.